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However, the phenotypes of shank3 mutant mice appear to be complex. Mice with shank3 mutations in
exon 9 did not display autistic behaviors, although they exhibited a reduction in the frequency of miniature
inhibitory postsynaptic currents (mIPSCs) in pyramidal neurons of the medial prefrontal cortex (mPFC),
[41]
which contrasts with the observed increase in mIPSC frequency in the hippocampus . The InsG3680
mutation in mice is associated with early-onset striatal synaptic transmission defects and impaired social
interaction, as well as distinct alterations in synaptic transmission that were also seen in the prefrontal
cortex of R1117X mutant mice . Additionally, there is a notable alteration in the composition of PSD in
[42]
adult R1117X and InsG3680 mutant mice. InsG3680 mutant mice exhibit a significant deficit in social
interaction at an early disease stage compared with R1117X mutant mice . The shank3G mouse model
[42]
demonstrates deficiencies in motor learning and coordination, while exhibiting typical grooming behavior
and an aversion to inanimate objects. However, social interaction deficits and anxiety-like behaviors are not
observed in this model, although synaptic transmission and plasticity are impaired in these mouse
[43]
-/-
models . Mice with Δe4-22 (deletions of exons 4-22) exhibited a deficiency of shank3 that can hinder the
metabotropic glutamate receptor 5 (mGluR5) - Homer scaffolding, leading to abnormalities in the cortico-
striatal circuitry that are responsible for learning deficits and the manifestation of core behavioral
characteristics associated with ASD . The deficiency of shank3 exon 9 in rats results in impaired long-term
[44]
social memory and attention deficits. Consistently, synaptic plasticity deficits are observed in these rats,
from the hippocampus to the prefrontal cortex . In line with the critical role of shank3 in synaptic
[45]
function, shank3-deficient rats (exons 11-21) exhibited a decrease in spine density and alterations in
synaptic proteins . However, these mutant rats display normal social interaction behavior, despite
[46]
impaired social memory, as well as learning and memory deficits in this rat model .
[46]
Rodent models with shank3 mutations provide a valuable tool for understanding the function of shank3 and
its role in ASD. For instance, these models have demonstrated that mutations or deletions of the shank3
gene affect synaptic signal transmission and synaptic protein expression in various brain regions, such as
the striatum, hippocampus, and prefrontal cortex. However, one notable finding is that unlike the severe
clinical symptoms observed in humans with SHANK3 haploinsufficiency, shank3 mice show no or only
+/-
very mild phenotypes. The abnormal behavioral phenotypes in mice are almost exclusively found in
homozygous mutants [44,47,48] . Additionally, the inconsistent behavioral phenotypes of rodent models with
shank3 mutations suggest that mutations in different exons of the shank3 gene and the nature of mutations
may account for variations in behavioral phenotypes [Table 1]. Despite the closer phylogenetic proximity of
rodents, such as mice and rats, to humans compared to fruit flies and zebrafish, significant disparities persist
in terms of rodent brain development, neural circuitry, and anatomy compared to the human brain. As a
result, several phenotypes associated with ASD display inconsistencies or contradictions across different
mouse or rat models. Additionally, it is important to recognize the potential impact of diverse genetic
backgrounds within the same species on the ASD-like phenotype triggered by shank3 mutations. Therefore,
there is a pressing need for more extensive research into the intricate pathogenic mechanisms that underlie
the neurodevelopmental impairment associated with ASD, which may be unraveled by using non-human
primate models that are closer to humans than small animals.

Monkey models with SHANK3 mutations
Macaca monkeys possess high-order cognitive and social functions thanks to their well-developed
neocortex. They are closer to humans in terms of their specialized brain function and structures than
rodents [47,53,54] . The value of using primate models to study ASD has been supported by the generation of
monkeys with altered expressions of MECP2 using lentivirus and TALEN -based methods. However, a
[56]
[55]
SHANK3-edited monkey model was not reported until 2017. To date, two monkey models of SHANK3
mutants have been established using CRISPR/Cas9-mediated gene-editing technology in cynomolgus
monkeys [51,52] . Despite the limited number of SHANK3 mutant monkeys generated, they provide important
insights into the function of SHANK3 and its role in ASD, which deserves a thorough discussion below.